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Unmasking the Annexin I Interaction from the Structure of Apo-S100A11

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Unmasking the Annexin I Interaction from the Structure of Apo-S100A11 View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Structure, Vol. 11, 887–897, July, 2003, 2003 Elsevier Science Ltd. All rights reserved. DOI 10.1016/S0969-2126(03)00126-6 Unmasking the Annexin I Interaction from the Structure of Apo-S100A11 Anne C. Dempsey,1 Michael P. Walsh,2 some members of this family may act as calcium signal- and Gary S. Shaw1,* ing or sensor proteins (Drohat et al., 1998; Maler et al., 1Department of Biochemistry 2002; Otterbein et al., 2002; Sastry et al., 1998; Smith The University of Western Ontario and Shaw, 1998b). The S100 proteins are small acidic London, Ontario N6A 5C1 proteins of approximately 10–12 kDa in molecular weight Canada and found only in vertebrates. To date there have been 2 Department of Biochemistry and Molecular nineteen S100 proteins identified, most of which appear Biology to be cell specific (Donato, 2001; Heizmann, 1999; Heiz- University of Calgary mann et al., 2002). For example, S100B is concentrated Calgary, Alberta T2N 4N1 in glial cells (Petrova et al., 2000), while S100P is located Canada mainly in placental tissue (Becker et al., 1992). Several of the S100 proteins have also been linked with disease states such as Alzheimer’s and rheumatoid arthritis, Summary usually via the overexpression of the protein (Odink et al., 1987; Van Eldik and Griffin, 1994). However, the cause S100A11 is a homodimeric EF-hand calcium binding of the overexpression and details of the roles of these protein that undergoes a calcium-induced conforma- proteins in disease is still uncertain. Other S100 proteins tional change and interacts with the phospholipid have been shown to interact with a variety of proteins binding protein annexin I to coordinate membrane as- such as tubulin (Garbuglia et al., 1999), annexins I, II, sociation. In this work, the solution structure of apo- and VI (Bianchi et al., 1992; Garbuglia et al., 1998; Gerke, S100A11 has been determined by NMR spectroscopy 1990; Seemann et al., 1996), p53 (Baudier et al., 1992; to uncover the details of its calcium-induced structural Delphin et al., 1999), and actin (Fujii et al., 1990), and change. Apo-S100A11 forms a tight globular structure are proposed to regulate processes such as assembly, having a near antiparallel orientation of helices III and phosphorylation, and membrane interaction. IV in calcium binding site II. Further, helices I and IV, S100A11 (S100C, calgizzarin) is a member of the S100 and I and I؅, form a more closed arrangement than family, which is often expressed in smooth muscle (Allen observed in other apo-S100 proteins. This helix arrange- et al., 1996; Scho¨ nekess and Walsh, 1997; Seemann et ment in apo-S100A11 partially buries residues in heli- al., 1996). S100A11 has been shown to interact with the ces I (P3, E11, A15), III (V55, R58, M59), and IV (A86, phospholipid binding protein annexin I in a calcium- C87, S90) and the linker (A45, F46), which are required sensitive manner (Seemann et al., 1996). In this mecha- for interaction with annexin I in the calcium-bound nism, the N-terminal helix of annexin I is released from state. In apo-S100A11, this results in a “masked” bind- interaction with the third repeat in the annexin molecule ing surface that prevents annexin I binding but is un- (Gerke and Moss, 2002). This helix then associates with covered upon calcium binding. calcium-bound S100A11 where it could act as a bridge to link pairs of phospholipid-containing membranes. In the absence of calcium, annexin I has negligible affinity Introduction for S100A11 or the phospholipid matrix. Consistent with this role and an intracellular location near the interior of The calcium ion acts as an important second messenger membranes, the calcium affinity for S100A11 is lower controlling integral cellular events such as neurotrans- Ca Ϫ4 M) than that typically found for other S100 10ف Kd) mitter release, vision, and muscle contraction. In many Ϫ Ϫ M), because the local calcium 6 10–5 10ف proteins (K Ca cases, a member of the EF-hand family of calcium bind- d concentration appears higher near the membrane. It is ing proteins plays an intermediary role in these pro- likely the affinity of S100A11 for calcium is increased in cesses through either calcium-dependent interactions the presence of a target protein, as has been noted for with selected target proteins or maintenance of intra- calmodulin (Martin et al., 1996; Olwin and Storm, 1985; cellular calcium levels. In the first mechanism, calcium Yazawa et al., 1987). In support of this hypothesis, the fold in-10ف binding to an EF-hand protein results in a significant affinity of S100A11 for calcium is enhanced conformational change in the protein and a change in the presence of the hydrophobic probe 2-p-toluidinyl- its surface properties, facilitating the interaction with naphthalene-6-sulfonate (Allen et al., 1996). Other stud- other proteins. The EF-hand proteins troponin-C and ies have shown that S100A11 associates with F-actin, calmodulin are members of this category of “sensor” where it can inhibit its myosin Mg2ϩ-ATPase activity proteins (Ikura, 1996), having their respective interac- (Zhao et al., 2000). tions with troponin-I (McKay et al., 1997) and myosin S100A11, like most S100 proteins, is a dimeric protein, light chain kinase (among others; Ikura et al., 1992) con- with each monomer comprising two helix-loop-helix mo- trolled by calcium binding. tifs that coordinate the calcium ions. Calcium binding Recently, three-dimensional structures of proteins in site I is comprised of helices I and II and a 14 residue the S100 family of EF-hand proteins have indicated “pseudo” calcium binding loop, while site II contains helices III and IV with a 12 residue canonical calcium *Correspondence: [email protected] binding loop. Calcium binding to most S100 proteins Structure 888 Figure 1. Selected Regions of 600 MHz NMR Spectra Used for the Backbone Assignment of Apo-S100A11 The spectra show 15N planes for the residues N40–A44 at the C terminus of helix II and start of the linker. For each pair of planes, the CBCA(CO)NH is shown on the left and the HNCACB is shown on the right. The C␣ and C␤ for the indicated residue are shown on the HNCACB spectra and the corresponding C␣ and C␤ for the previous (i Ϫ 1) residue are shown in the CBCA(CO)NH. The spectrum was collected on a 1.0 mM apo-S100A11 sample in 90% H2O/10% D2O containing 50 mM KCl, 10 mM dithiothreitol (pH 7.25) at 35ЊC. causes a significant reorientation of one or more of the are facilitated by an open conformation of helices III helices, resulting in an exposure of hydrophobic resi- and IV, which are near perpendicular to one another. dues previously buried in the apo-state (Maler et al., Comparison to other apo-S100 protein structures sug- 2002; Smith and Shaw, 1998a). For example, calcium gests that these helices have reoriented upon calcium binding to human S100B triggers a reorientation of helix binding in order to create a hydrophobic cleft for target III with respect to helix IV and extends the ␣ helix in binding. However, the absence of an S100A11 structure helix IV by one turn (Drohat et al., 1998; Matsumura et in the calcium-free state and the differences from the al., 1998; Smith and Shaw, 1998b). This results in the calcium-bound S100B complexes makes the details of exposure of several hydrophobic residues in the C termi- the conformational change and protein-protein interac- nus and linker region of the protein, providing a surface tions in S100A11 difficult to assess. In this work, we for target interaction. In S100A6, calcium binding in- have determined the three-dimensional structure of rab- duces a less dramatic conformational change, although bit apo-S100A11 by NMR spectroscopy in order to iden- a hydrophobic surface is still exposed. In general, it is tify the conformational change that occurs in this protein thought that differences in the hydrophobic surfaces and identify residues that confer specificity for target between S100 proteins and the magnitude of the confor- protein binding. The structure reveals that helices I and mational change confer target specificity for a variety IЈ at the dimer interface of apo-S100A11 form a more of different proteins. closed arrangement compared to other apo-S100 pro- Recently, the crystal structure of calcium-bound teins, while helices III and IV form a near antiparallel S100A11 in complex with an N-terminal peptide of annexin arrangement. This conformation of apo-S100A11 buries I has been determined (Rety et al., 2000). The structure residues required for annexin I interaction found in heli- shows that the annexin interface occurs through interac- ces I, III, and IV and the linker region. Upon calcium tions with the linker and helices III and IV of one monomer, binding to S100A11, these residues are unmasked to and helix I of the other monomer in S100A11. Thus, the reveal a stunning contiguous binding surface. annexin molecule “bridges” the two S100 monomers. This interaction is very different from the interactions of Results and Discussion another S100 protein, S100B, with two of its targets, p53 (Rustandi et al., 2000) and a 12 residue synthetic The backbone and side chain resonance assignments peptide, TRTK-12 (McClintock and Shaw, 2003). In both for apo-S100A11 (Rintala et al., 2002) were determined of these cases, there are no interactions with helix I in by the collection and analysis of a set of two- and three- S100B, and each target peptide interacts with only one dimensional NMR experiments.
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